Smoking remains the leading cause of preventable diseases and death in the US, and is known to be heritable. This application aims to develop a set of nicotine addiction cell lines based on clinically defined imaging phenotype and genotype. Our goal is to test that neuronal electrophysiological response to nicotinic agonists will be associated with the strength of the clinical imaging based circuit phenotype in patients with severe nicotine addiction and carry smoking related risk alleles. Our innovation here is to closely link these cell lines with state-of-the art clinical measures of nicotine addiction, so that we coud iteratively test electrophysiological phenotypes of the cells that are likely underlying key clinicl nicotine addiction measures. PUBLIC HEALTH RELEVANCE: Smoking remains the leading cause of preventable diseases and death in the US. This application aims to develop nicotine addiction cell lines based on clinically defined imaging phenotype and genotype. Our goal is to identify electrophysiological mechanisms underlying clinical nicotine addiction.